We are searching for compounds and mechanisms that cause oncogene-selective lethality. Such compounds eliminate tumor cells harboring specific oncogenic mutations, but have minimal effects on normal cells lacking these mutations. In this project, we propose to screen for new compounds that are selectively lethal to tumor cells expressing the RAS oncogenes. It is important to note that these compounds do not directly inhibit RAS proteins or the RAS pathway, but rather cause cell death specifically in tumor cells containing oncogenic RAS proteins. Using high-throughput screening of 70,000 compounds in isogenic, engineered tumor cell lines, we discovered three compounds selectively lethal to oncogenic-RAS-expressing cells. With the tools of synthetic chemistry, molecular biology and proteomics, we discovered that voltage dependent anion channels (VDACs) are target proteins for two of these compounds. We found that these compounds act through mitochondrial VDAC proteins to cause an oxidative, non-apoptotic death. These compounds thus revealed that oncogenic RAS signaling causes increased VDAC levels and that VDACs are novel gain-of-function targets for cancer therapeutics. Our results suggest that VDAC ligands are potential chemotherapeutic agents for the treatment of cancers with activated RAS signaling. We propose to find new RAS-selective lethal compounds and determine whether they act through VDAC proteins or through new mechanisms. New VDAC ligands would be valuable in trying to translate these compounds into potential therapeutics. [unreadable] [unreadable] [unreadable]